Studies are being conducted to determine the mechanism(s) by which commonly used anesthetics produce tissue damage and to determine what factors aggravate or ameliorate the tissue damage. The major emphasis in this project during the past year has been to study the effects of hypoxia on halothane induced liver damage. The major emphasis in this project during the past year has been to study the effects of hypoxia on halothane induced liver damage. An animal model of halothane hepatotoxicity was developed and termed hypoxic model. Phenobarbital pretreated rats are anesthesized with 1% halothane in 14% O2 for 2 hrs. Within 24 hrs, severe centrolobular hepatic necrosis is evident. Accompanying this halothane induced necrosis is an elevation of SGPT, a reduction in liver microsomal cytochrome P-450 and a 5 fold increase in urinary halothane derived fluoride levels. The elevated urinary F- levels indicate that hypoxia qualitatively and quantitatively alters halothane biotransformation. Two volatile metabolites of halothane (CF2=CHCl and CF3CH2Cl) have been isolated from the liver of rats exposed to halothane. Pretreatment of rats with liver microsomal inducing agents increases the formation of these metabolites. One of these metabolites has been shown to produce liver necrosis when infused into the portal vein. Studies in the coming year will focus on determining if the production of these volatile metabolites correlates with halothane induced liver damage. The subcellular localization of the enzymes that produce these metabolites will also be determined. A major emphasis will focus on determining if inhibitors of drug metabolizing enzymes influence the production of these volatile metabolites as well as halothane induced hepatotoxicity.